Glucose uptake by the liver is now recognized as being an important component of glucose homeostasis and to be defective in the diabetic state thereby contributing to post-prandial hyperglycemia, elevated HBA1c, and cardiovascular disease. It is difficult to measure hepatic glucose uptake in man and as a result its regulation is not well understood. Net hepatic glucose balance (NHGU) can be measured in the conscious dog and metabolic control in the dog is known to resemble that in the human. Our goal therefore is to explore the regulation of NHGU and muscle glucose uptake in the conscious dog. We will break metabolic feedback loops using pharmacologic and surgical approaches and we will assess hepatic and limb glucose metabolism in vivo using arteriovenous difference and tracer techniques. We will assess the physiological response to the designated perturbation and we will concurrently measure the biochemical changes which accompany it by taking hepatic biopsies. The aims of the proposed studies are to assess 1) the role of brain insulin and glucose levels in regulating hepatic uptake and disposition of glucose;2) the role of signaling molecules (NO, GLP-1) in regulating hepatic uptake &disposition of glucose;3) the role of the sympathetic, parasympathetic and serotonergic nervous systems in regulating the hepatic uptake and disposition of glucose;4) the effect of the hepatic glycogen level on the uptake and disposition of glucose by the liver and 5) the biochemical changes associated with the actions of glucose, the portal glucose signal and fructose on glucose uptake by the liver. Data from the proposed experiments will further our understanding of the control of NHGU in vivo and should be of value in the development of new therapeutic approaches to control of the glucose level in the individual with diabetes.